Novel compounds derived from taurine, process of their preparation and pharmaceutical compositions containing these

ABSTRACT

The present invention relates to compounds derived from taurine with non-steroidal anti inflammatory activity. 
     In a first embodiment, the present invention relates to compounds derived from taurine, in which taurine is bound directly by means of an amide bond or through an spacing group, to a compound selected from the group of non-steroidal anti inflammatory compounds, cited as derived from taurine presenting the Formula (I): 
     
       
         
         
             
             
         
       
     
     in which R means the component with non-steroidal anti inflammatory activity. 
     In a second embodiment, the invention provides a process for obtaining the compounds of Formula (I) by reaction of taurine with a compound belonging to the group of non-steroidal anti inflammatory (NSAIs), in order to obtain a compound derived from taurine by direct bond or through a spacing group of the taurine to the NSAI. 
     The invention also relates to the pharmaceutical compositions comprising at least one compound derived from taurine presenting non-steroidal anti inflammatory activity.

FIELD OF THE INVENTION

The present invention relates to novel drugs derived from taurine,preferentially for use as non-steroidal anti inflammatory (NSAI)adjuvants, the obtaintion of such novel drugs and their use inpharmaceutical compositions for treatment of medical conditionsincluding inflammatory processes, rheumatoid arthritis, ulcerativecolitis, Chron's disease, and their use as antipyretics, analgesics andplatelet anti aggregants.

BACKGROUND OF THE INVENTION

The inflammatory processes have always received great attention inscience for being the first biological sign in any abnormality state ofa medical condition.

Inflammation is fundamentally a protection response triggered byphysical, chemical and biological stimulus that may lead to disturbancesthat can culminate in tissue necrosis.

In the '70s, after Vane and colleagues (see Vane, J. R. (1971).“Inhibition of prostaglandin synthesis as a mechanism of action foraspirin-like drugs”. Nature-New Biology 231(25):232-5) demonstrated theparticipation of prostaglandins as mediators of inflammation, throughits inhibition by acetyl salicylic acid, the research have intensifiedwith the development of uncountable families of anti inflammatory drugs,especially the ones known as non-steroidal anti inflammatory (NSAI)drugs (see ROBERTS, L. J.; MORROW, J. D. “Analgesic-antipyretic andantiinflamatory agents and drugs employed in the treatment of gout”. In:HARMAN, J. G.; LIMBIRD, L. E. (Eds.). Goodman & Gilman's: thepharmacological bases of therapeutics. New York: MacGraw-Hill, 2001, p.687-732).

The NSAIs are drugs largely used, constituting an important medicamentalresource in despite of the possibility of causing serious side effects,such as gastric irritations (high incidence) and hypertension, causingalso liver, kidney, spleen, blood and bone marrow damages (see RANG, H.P.; DALE, M. M.; RITTER, J. M. Farmacologia. Fourth ed. Rio de Janeiro:Guanabara Koogan, 2001, p. 692).

The mechanism of action for NSAI drugs encompasses the inhibition ofcyclooxygenases (COX), denominated COX-1 (constitutive form and itsinducible form COX-2), interfering in the synthesis of prostaglandins(PG) and reducing the inflammatory reactions.

The prostaglandins perform important physiological functions; among themis gastrintestinal cytoprotection and vascular homeostasis.

COX-1 is responsible for the synthesis of cytoprotector prostaglandinsof the gastrintestinal tract and for the synthesis of tromboxans thatparticipate in the formation of platelets aggregation (see Allison,Howatson, Torrence, Lee and Russell. “Gastrointestinal Damage Associatedwith the Use of Nonsteroidal Antiinflammatory Drugs”. N. Engl. J. Med.(1992) Vol. 327, pp. 749-754). Regarding COX-2, it is known that it ischaracterized for presenting a short life, and its production occursfrom stimulus in response to endotoxins and cytotoxins. It is importantto highlight the fact that COX-2 inhibits the prostaglandins responsiblefor biosynthesis in inflammatory cells (monocytes and macrophages) aswell as in the central nervous system (see Masferrer, Zweifel, Manning,Hauser, Leahy, Smith, Isakson and Seibert, “Selective Inhibition ofInducible Cyclooxygenase-2 in vivo is Antiinflammatory andNonulcerogenic”, Proc. Natl. Acad. Sci. U.S.A. (1994) Vol. 91, pp.3228-3232; Vane, Mitchell, Appleton, Tomlinson, Bishop-Bailey, Croxtalland Willoughby, “Inducible Isoforms of Cyclooxygenase and Nitric OxideSynthase in Inflammation”, Proc. Natl. Acad. Sci. U.S.A. (1994) Vol. 91,pp. 2046-2050; Harada, Hatanaka, Saito, Majima, Ogino, Kawamura, Ohno,Yang, Katori and Yamamoto, “Detection of Inducible Protaglandin HSynthase-2 in Cells in the Exudate of Rat Carrageenin-Induced Pleurisy”,Biomed. Res. (1994) Vol. 15, pp. 127-130; Katori, Harada, Hatanaka,Kawamura, Ohno, Aizawa and Yamamoto, “Induction of Prostaglandin HSynthase-2 in Rat Carrageenin-Induced Pleurisy and Effect of a SelectiveCOX-2 Inhibition”, Advances in Prostaglandin, Thromboxana, andLeukotriene Research (1995) Vo. 23, pp. 345-347; and Kennedy, Chan, Culpand Cromlish, “Cloning and Expression of Rat Prostaglandin EndoperoxideSynthase (Cyclooxigenase-2) cDNA”, Biochem. Biophys. Res. Commun. (1994)Vol. 197, pp. 494-500).

The traditional NSAI drugs such as ASA (acetyl salicylic acid),diclophenac, ibuprophen, and naproxen inhibit COX-1 and COX-2. Thisnon-selectivity of NSAI drugs leads also to the inhibition ofprostaglandins, which are important for participating in gastricprotection.

In order to reduce side effects caused by traditional NSAI drugs, anenormous quantity of COX-2 selective drugs (COX-2 inhibitors) have beenresearched, some of which are available in the market.

There are evidences that the reduction of the gastrintestinal sideeffects caused by COX-2 selective inhibitors leads to an adaptativeresponse to the gastric damage, which does not occur when using COX-1inhibitors (see PESKAR, B. M.; EHRLICH, K.; PESKAR, B. A. “Interactionof cyclooxigenase-2 inhibitor and salicylate in gastric mucosal damage”,European Journal of Pharmacology, v. 434, n. 1-2, p. 65-70, 2002;YAMAMOTO, H. et al. “Inducible types of cyclooxigenase and nitric oxidesynthase in adaptive cytoprotection in rat stomachs”, Journal ofPhysiology, v. 93, p. 405-12, 1999).

On the other hand, there are no studies that demonstrate the differencesin efficacy among the COX-2 selective inhibitors, even though there isproof of the reduction of the adverse gastrintestinal effects caused bythem. The problem with these inhibitors appears when it is taken intoconsideration the adverse cardiovascular effects reported by Stacy etal. (see STACY, Z. A.; DOBESH, P. P.; TRUJILLO, T. C. “Cardiovascularrisks of cyclooxygenase inhibition”, Pharmacotherapy, v. 26, n. 7, p.919-938, 2006), being, for this reason, preferred the use ofnon-selective anti inflammatory drugs.

In fact, the safety of known COX-2 inhibitors have been questioned. Themost famous event occurred with the “blockbuster” rofecoxib, withcommercial name of Vioxx®, produced by Merck laboratories, which wasremoved from the market in 2004 after clinical researches demonstratedthat it caused a higher risk of heart attack and brain stroke. Otherthree COX-2 inhibitors that are available in the Brazilian market,celecoxib (Celebra®), valdecoxib (Bextra®) and etoricoxib (ARCOXIA®) areunder intense clinical studies in order to verify the safety of theiruse. In addition, in Apr. 5, 2005, FDA (Food and Drug Administration)has suspended the commercialization of Bextra in the United States andalso, in May, 2007, it did not approve the commercialization of Arcoxia.

For all these reasons, the NSAI drugs are still the ones largely used asan important medicamental resource, in spite of the possibility ofcausing serious known side effects (principally gastric ulceration).

It is still worth mention the role of nitric oxide in the inflammatoryprocesses. In fact, nitric oxide (NO) began to received attention byphysiologists with the discovery, in 1986, of Ignaro and collaboratorsthat have described its function as a endothelium derived relaxationfactor (EDRF) and have proposed the participation of nitric oxide in theprocesses of pro inflammatory actions with effects in the vasodilatationand of stimulus of prostaglandins production, as well as antiinflammatory action in order inhibit neutrophyls and platelets, being,therefore, dependent of an immuno-regulated factor (see MONCADA, PALMER,& HIGGS, “The discovery of nitric oxide as the endogenousnitrovasodilator”, Hypertension, v. 12, p. 365-372, 1988).

The nitric oxide is a colorless gas, paramagnetic, water soluble in theproportion of 2-3 moles per dm³ and presents a boiling point around−141.7° C. It is produced in vivo through interaction, catalyzed byenzymes (nitric oxide synthase—NOS), with molecular oxygen andL-arginine (as substrate). Nitric oxide becomes a free radical that,differently from many other free radicals, does not dimerize in thegaseous phase at room temperature and pressure, even though in theliquid state it may form N₂O₂. When the loss of an electron of thenitric oxide free radical occurs leads to the formation of the nitrosilion (NO⁺).

Among the evident chemical properties of nitric oxide, it can behighlighted the possibility of radical formation and, consequently, itsbiological participation as electrophile, oxidant agent, salt andcomplex formation agent. In the biological system, the radical form ofnitric oxide is associated to other species of nitrogen compounds, suchas nitrite (NO₂), nitrate (NO₃) and peroxynitrite (NO₄).

The constitutive isoforms of nitric oxide (cNOS) are subdivided inneuronal (nNOS) and endothelial (eNOS) and, depending in which tissuethey are found, they are calcium dependent and can be activated by thecalcium binding protein (calmodulin-CaM), through agonists such asacetylcholine (ACh), adenine diphosphate (ADP), bradicinine (Bk) andglutamate (see BARRETO, R. L.; CORREIA, C. R. D.; MUSCARA, M. N., “ÓxidoNítrico: propriedades e potenciais usos terapéuticos”, Quimica Nova, v.28, n. 6, p. 1046-1054, 2005).

In addition, nitric oxide acts as a transmitter of the periphericalnervous system and of the urogenital and gastrintestinal tracts.

The induced isoform of nitric oxide (iNOS) is calcium independent and isproduced, in high concentrations, by means of activation with bacterialtoxins, interpheron and interleukins.

In the defense system, NO is produced by mast cells, macrophages,Kupffer cells and neutrophyls, causing oxidative lesions in the targetcell by means of attacking the proteins that are complexed to themembrane.

It is also known the technique to reduce the intestinal mucous membranedamage caused by the anti inflammatory active principles and, at thesame time, guaranties a satisfactory absorption of such activeprinciples, through the addition of arginine and similar aminoacids tothe pharmaceutical compositions that present protective activity againstintestinal mucous membrane damage (see Y. Kinouchi, N. Yata, Biol.Pharm. Bull., 19(3), pp. 375-378 (1996)).

In fact, it is known that L-arginine (NO precursor) protects the gastricmucous membrane from lesion formation, which mechanism probably involvesan increase of the blood flux due to the dilatation of adjacentcapillars (see KALIA, N. et al. “L-Arginine protects and exacerbatesethanol-induced rat gastric mucosal injury”, Journal Gastroenterologyand Hepatology, v. 15, n. 8, p. 915-24, 2000).

Studies performed with the introduction of L-arginine in the treatmentwith ibuprophen demonstrate a reduction of the oxidative stress and theinfiltration of neutrophyls in the gastric mucous membrane, reducing thelesion caused by the anti inflammatory drug. This injury mechanism thatdepends of the microcirculation is of extreme importance for events ofgastrintestinal toxicity caused by NSAI drugs that, in parallel to itstherapeutic action, cause damage to the mucous membrane throughinflammation mechanism and oxidative lesion monitored by the activity ofmieloperoxidases, by the neutrophyllic activation rate, or by lipidperoxidation and activation of xantine oxidase, glutathione peroxidaseand superoxide dismutase.

An explanation of the protective activity of L-arginine is theoccurrence of a local action that is probably related to the inhibitionof the oxidative stress derived from the xantine oxidases, but not tothe blockage of the production of free radicals by nuclear polymorphleucocytes (see JIMENEZ, M. D. et al. “Role of L-arginine inibuprofen-induced oxidative stress and neutrophil infiltration ingastric mucosa”, Free Radical Research, v. 38, n. 9, p. 903-111, 2004).

It is also known that taurine acts in the inflammatory process due toits important activity which is of inhibiting the NO and E2-typeprostaglandins production, acting in the suppression of the induciblenitric oxide synthase (iNOS) and in the expression of COX-2 (see LIU, Y.et al. “Taurine Chloramine Inhibits Production of Nitric Oxide andProstaglandin E2 in Actiated C6 Glioma Cells by Supressing InducibleNitric Oxide Synthase and Cyclooxigenase-2 expression”, Molecular BrainResearch, v. 59, p. 189-195, 1998), as well as in the inhibition of theperoxide ions (see CHAEKYUN, K. et al., “The Production of SuperoxideAnion and Oxide by Cultured Murine Leukocytes and the Accumulation ofTNF-α in the Conditioned Media is Inhibited by Taurine Chloramine”,Immunopharmacology, v. 34, p. 89-95, 1996).

Another action of taurine is related to the reduction of thehyperanalgesic effects (see THOMAS, G. “Óxido Nítrico” In: QuímicaMedicinal: Uma Introdução. Rio de Janeiro: Guanabara Koogan, p. 337-61,2003), leading to normal levels of NO production, impeding, this way,the active and exacerbated presence of iNOS and inhibiting thearachidonic acid cascade. In fact, in 2001, Palumbo, Cioffi and D'Ischiarequested patent for the NOS inhibitory compounds envisioning diverseuses, including inflammatory processes, reinforcing the safetyexpectation of this therapy (CAN 137:346227; AN 2002:894293; Italianapplication ITRM20000039 A, published in Jul. 24, 2001), confirming theresults of Moncada and Higgs (see MONCADA, S.; HIGGS, E. A. “Molecularmechanisms and therapeutic strategies related to nitric oxide”, FASEBJournal, v. 9, p. 1319-1330, 1995), about the utilization of nitricoxide synthase inhibitors, which represents an advance in the therapy ofinflammatory conditions.

The inhibition of the oxidative stress can be explained by the systemicaction of aminoacids. In this context, taurine have been presentingadvantages related to the systemic action of gastro protection, probablythrough the suppression of free radicals derived from oxygen, whichperform important physiopathologic role in the acute ulceration inducedby NSAI drugs and ischemic reperfusion.

The experiment results using taurine as anti oxidant in the intragastricadministration in rats pre-treated with 250 mg/kg or 500 mg/kg from 1(one) to 3 (three) days before hemorrhagic lesion induction by 25 mg/kgof indometacin presented a lesion reduction with the inhibition of lipidperoxidation, besides the inhibition of neutrophyls activity (see SON,M. et al. “Protective effect of taurine on indometacin-induced gastricmucosal injury”, Adv Exp Med Biol, v. 403, p. 147-55, 1996).

It is known, still, that taurine provides a significant reduction of theacid secretion and the increase of the bicarbonate liberation from thelumen due to mechanisms of regulation between the production of nitricoxide and prostaglandins, with a compensatory feedback being kept in thestomach (see TAKEUCHI, K. et al. “Nitric oxide and prostaglandins inregulation of acid secretory response in rat stomach following injury”,Journal of Pharmacology Experimental and Therapeutic, v. 272, n. 1, p.357-63, 1995).

In addition, it is known that the anti ulcerative activity is closelyrelated to the improvement of the blood flux reduction in the mucousmembrane due to the nitric oxide synthesis disturbance, in which theinfluence of anti ulcerogenic drugs is largely studied, as in the caseof the [2,4-diamino-6-(2,5-dichlorophenyl)-S-thiazin]maleate. Accordingto Takashi et al. (TAKASHI, K. et al. “Irsogladine preventsmonochloramine-induced gastric mucosal lesions by improving the decreasein mucosal blood flow due to the disturbance of nitric oxide synthesisin rats”, Journal of Pharmacological Sciences, v. 93, p. 314-20, 2003)the action proposal can be demonstrated through the use of constitutivenitric oxide synthase (cNOS) inhibitors or non selective inhibitors suchas N^(G)-nitro-L-arginine methyl esther (L-NAME) and inducible nitricoxide synthase (iNOS) selective inhibitors, for example, theaminoguanidin, where the[2,4-diamino-6-(2,5-dichlorophenyl)-S-thiazin]maleate blocks theinhibitory action of cNOS without affecting the action of iNOS which isresponsible for cellular recruiting.

As mentioned previously, the nitric oxide perform an important role inthe protection of gastric ulceration induced by non steroidal antiinflammatory drugs by means of mechanisms that go beyond acid secretion,leading to a novel route for the treatment of gastric ulceration causedby anti inflammatory drugs. In pre clinic tests using the indometacin ascontrol group of ulceration, it was verified that an 80% increase ingastric acidity with a 22% reduction of nitric oxide (measured asnitrite) occurs. On the other hand, the use of L-NAME does not affectgastric acidity, but causes a 50% reduction in the normal concentrationsof nitric oxide and, consequently, the lesion rate doubles (see KHATTAB,M. M.; GAD, M. Z.; ABDALLAH, D. “Protective role of nitric oxide inindometacin-induced gastric ulceration by a mechanism independent ofgastric acid secretion”, Pharmacological Research, v. 43, n. 5, p.463-67, 2001).

The peripherical vascular tonus homeostasis is of great importance inorder to maintain the integrity of functional adjacent tissues where themanipulation of the process of NO up-down regulation can lead tothrombosis and ischemic complications, in case of low NO production.

It is important to highlight that, in analyzing the parameters of NOmeasurements in separate, its subfamilies and production moments must berelated to enzymatic activity. This can be an answer to the fact thatthe use of a simple precursor, such as L-arginine it is not capable ofpreventing lesion formation in the gastric mucous membrane.

Therefore, the enzymatic substrate (L-arginine) can even increase thepresence of NO in exacerbated form in pro inflammatory cells, which, insome way, makes this measure inefficient for blocking free radicalsinduced in the gastrintestinal inflammatory process.

In this context, taurine plays the role of mediator of a microcirculatory feed-back, besides acting in the inhibition of the enzymaticisoform induced in the inflammatory process. This isoform is responsiblefor the oxidative stress, then confirming the activity of taurine asgastrintestinal anti oxidant and anti inflammatory drug.

In the investigation of the gastro protector compounds, it was observedthat taurine increases cellular resistance in 21%, with maintenance ofmembrane, mitochondria and nuclear damages integrity (see NAGY, L. etal. “Investigation of gastroprotective compounds at subcellular level inisolated gastric mucosal cells”, American Journal Physiology andGastrointestinal Liver Physiology, v. 279, n. G1, 201-08, 2000) whichreinforces, through elucidation of gastric mucous membrane atsubcellular level, the use of taurine as gastro protector compound.

Another proposal of mechanism of action for cytoprotection is based onthe adaptation of the endogenous response mediated by prostaglandinswithout involving the protection pathway effect mediated by nitricoxide. This hypothesis was presented for the activity of L-arginine (NOprecursor) against gastric injury, caused in rats, induced by the oraladministration of hydrochloric acid (see TAKEUCHI, K. et al.“Cytoprotective action of L-arginine against HCL-induced gastric injuryin rats: Involvement of nitric oxide?”, Japan Journal Pharmacology, v.61, p. 13-21, 1993). The advantage of taurine over L-arginine becomesmore evident from the analysis of the results of its use in thereduction of damages to the gastric mucous membrane, because it does notpresent NO precursor activity.

Although the participation of prostaglandins and nitric oxide in theinhibition of lesion formation induced by necrotic agents is known,there is no clear correlation with the importance degree of thesemediators. Nitric oxide inhibition experiments (L-NAME) with supplementof E₂ 16,16-dimethyl prostaglandin do not cause damage. On the otherhand, prostaglandin inhibition with supplement of nitric oxide donor isnot sufficient for maintenance of gastric mucous membrane integrity (seeUCHIDA, M. et al. “Nitric oxide donating compounds inhibit HCl-inducedgastric mucosal lesions mainly via prostaglandin”, Japan JournalPharmacology, v. 85, p. 133-38, 2001). This study confirms the mostevident adverse effect in the therapeutic use of anti inflammatorydrugs, as well as the difficulty in lesion reversion orgastroprotection.

Taurine acts in the inflammatory process due to its important activityin inhibiting NO and E2-type prostaglandins (PGE₂) production and inacting in the suppression of inducible nitric oxide synthase (iNOS) andin the expression of type-2 cyclooxygenase (see LIU, Y. et al. “Taurinechloramine inhibits production of nitric oxide and prostaglandin E₂ inactivated C6 glioma cells by suppressing inducible nitric oxide synthaseand cyclooxigenase-2 expression”, Molecular Brain Research, v. 59, p.189-195, 1998), as well as in the inhibition of peroxide ions production(see CHAEKYUN, K. et al. “The production of superoxide anion and oxideby cultured murine leukocytes and the accumulation of TNF-(in theconditioned media is inhibited by taurine chloramine”,Immunopharmacology, v. 34, p. 89-95, 1996).

Many attempts to interfere in the process of gastric lesion formationcaused by the NSAI drugs have been made. In the U.S. Pat. No. 7,008,920it is described the pharmaceutical association between NSAI drugs, bileacid salts and taurine or polyamines in order to reduce thegastrintestinal damage induces by drugs and the increase of theirwater-solubility.

It is also known that taurine, besides acting against gastric damage(see SENER, G. et al. “Protective effect of taurine againstalendronate-induced gastric damage in rats”, Fundamental & ClinicalPharmacology, v. 19, p. 93-100, 2004), it also attenuates kidneyhypertension (see HAGAR, H. H.; ETTER, E. E.; ARAFA, M. “Taurineattenuates hypertension and renal dysfunction induced by cyclosporine Ain rats”, Clinical and Experimental Pharmacology and Physiology, v. 33,p. 189-196, 2006).

Another important aspect in the search for compounds that attenuate theadverse effects of NSAI drugs and potentate the beneficial effects ofthese drugs is the development of viable processes of obtaintion undertechnical and economical point of view. Therefore, numerous researchesare being developed in order to obtain novel compounds using, mainly,the molecular modification techniques. Among the obtaintion processes,it is of great importance the latentiation that has the purpose ofdeveloping the prodrugs that consist in inactive vehicle forms and thatrelease the drug in vivo after biotransformation (see WERMUTH, C. G.“The Practice of Medicinal Chemistry”, London: Academic Press, 2^(a) ed,2003. 768 pages; KROGSGAARD-LARSEN, P., BUNDGAARD, H. “A textbook ofdrug design and the development”, Harwood: Academic Publish, 1991, 643pages; SILVA, A. T. A. et al. “Advances in prodrug design”, MedicinalChemistry. v. 5, n. 10, p. 893-914, 2005).

The most current therapeutic chemical compounds have been producedthrough the latentiation of the original drug, particularly throughestherification and amides formation. In a simpler way, it can be saidthat latentiation is an organic synthesis process that seeks to modifythe molecule of an active compound or original drug in order to optimizeits pharmacokinetic properties and/or reduce its toxicity.

In the past few years, latentiation has become one of the main tools forthe development of chemiotherapic drugs used in the treatment of themajor current diseases such as cancer and Acquired ImmunodeficiencySyndrome—AIDS. The search for latent drugs is justified by at least oneof the following reasons: (i) minimize the pharmacokineticinconveniences belonging to the original drug, (ii) reduce the hightoxicity of the original drug, (iii) perfect the weak chemical stabilityof the original drug, (iv) improve the water-solubility of the originaldrug, (v) reduce the inconveniences of odor and taste of the originaldrug and (vi) make it possible the obtaintion of difficultpharmaceutical formulations due to the original drug.

The latent drugs, called prodrugs, correspond to original drugs that arechemically transformed to an inactive derived compound through chemicalreactions, enzymatic reactions or both. The prodrug is converted intothe original drug inside the organism prior or after reaching its actionspot.

The prodrug can be defined as any compound that undergoesbiotransformation before exhibiting its pharmacologic effects. Theprodrug as well as the analog of a drug present similar chemicalstructures, however the biological properties of these compounds differfrom the original drug regarding: (i) the activity, (ii) the potency,(iii) the bioavailability, (iv) the synthesis process, (v) the actionspectrum, and (vi) therapeutic index. The prodrug differs from theanalog drug due to the in vivo hydrolysable chemical bond and thetransporter group.

Among the various prodrugs obtaintion methods, estherification is themost employed one, followed by amide, imide and carbamate formation.Currently, drug functional groups can be modified through chemicalreactions producing reversible groups heavily used in the development ofprodrugs.

Countless substitutions in known molecules as well as novel NSAI-deriveddrugs are described in the state of the technique seeking to improve notonly their adverse effects as well as their anti inflammatory potential.For example, the U.S. Pat. No. 5,905,073 described 5-ASA and otherNSAI-derived prodrugs for treating ulcerative colitis.

Among the commercially available NSAI drugs, diclophenac is one of themost used anti inflammatory drugs. In fact, diclophenac, discovered in1966 and described in the U.S. Pat. No. 3,558,690, is one of the bestseller drugs in the world and its efficacy and safety is established inthe anti inflammatory therapy field. Various substitutions have alsobeen made in 2-arylaminophenylacetic acids in order to reduce thedeleterious side effects of this active principle, being described inseveral patent documents, such as, for example U.S. Pat. No. 3,652,762;U.S. Pat. No. 4,173,577; U.S. Pat. No. 4,166,128; U.S. Pat. No.4,704,468; U.S. Pat. No. 5,475,139; WO 9404484; WO 9709977; WO 9600716and DE 345011.

The aceclophenac is an example of diclophenac prodrug, described in theU.S. Pat. No. 4,548,952, obtained through the estherification of thecarboxylic group by an small alkyl chain, in an attempt of reducing thedeleterious effects in the gastrintestinal tract when used in antiinflammatory therapies. For example, the U.S. Pat. No. 6,451,858described estherifications in 2-arylaminophenylacetic acids as anattempt of increasing its selectivity towards COX-2.

Other modifications in the diclophenac molecule were performed in orderto reduce undesired side effects or to increase its bioavailability tomake other administration options besides oral viable, being cited: (i)the U.S. Pat. No. 4,704,468 that describes double diclophenac prodrugslinked by polyethylene glycol-derived compounds in order to reduce thegastric effects and (ii) the U.S. Pat. No. 5,792,786 that describes NSAIdrugs estherifications with long chained fatty acids in order toincrease their bioavailability in topic use pharmaceutical forms.

Still in order to reduce the prejudicial effects caused by NSAI drugs inpatients presenting inflammatory disturbances, more recently, researcheshas been directed to the a more detailed study of the functionsperformed by nitric oxide in the biological systems. In this context,the U.S. Pat. No. 5,597,847 describes 2-arylaminophenylaceticacids-derived compounds that were nitrated in order to increase theiranti inflammatory potential seeking to provide nitric oxide in theinflammatory process. In a similar way, prodrugs with NO local releaseare described in the patent document WO 2006125016.

The WO 9109831 document describes NSAI-derived prodrugs with acid groupsobtained through anhydride formation among groups present in the NSAIdrug itself or in different NSAI drugs, such as ASA, SA (salicylicacid), sulindac, cetoprophen, indometacin, naproxen, fenoprophen,ibuprophen, diflunisal, tolmetin, flurbiprophen, suprophen.

Other prodrug obtaintion examples are presented in the U.S. Pat. No.5,681,964 that describes indometacin estherifications, resulting inreduction of gastric damages; in the U.S. Pat. Nos. 5,607,966 and5,811,438 that describe esther derived compounds and indometacin amidesused as antioxidants and 5-lipoxygenase inhibitors, without, however,presenting COX-2 selectivity; in the U.S. Pat. No. 6,399,647 thatdescribes indometacin-derived sulphonamidic compounds presenting anincrease in COX-2 selectivity; and in the U.S. Pat. No. 6,887,903 thatdescribes sulphonamidic derived compounds that act in other pathways ofthe inflammatory process as signaling molecules of nuclear polymorphneutrophyls and other interleukins.

In spite of this diversity of NSAI prodrugs have presented advantagesregarding the original drugs, there are still various deleteriouseffects that limit their use.

Taurine and other specific aminoacids present themselves as interestingdrug transporters, enabling an improvement not only in physico-chemical,but also reducing its adverse effects. The U.S. Pat. No. 5,059,699presents taxol-derived compounds (antineoplasic) and taurine to increaseits water-solubility, leading to the increase of its bioavailability andstability in chemiotherapeutical formulas. Other formula improvementexamples using taurine are based on salicylate-derived compounds (SA andASA) or in sulphonamidic-derived compounds as described in the documentsJP68003293 and JP68004331.

The limitations and disadvantages of known prodrugs and drugs led to thesearch for novel active principles disclosed herein, which minimizes thedeleterious effects of the NSAI drugs. Hence, the present inventionresults from the knowledge of mechanisms of action of the antiinflammatory drugs described by the therapeutic field, exploring theirpotential in the use of NSAI-derived drugs during chronic antiinflammatory treatments.

Therefore, the objective of the present invention is to improve thepharmacotherapeutic that involves acute and chronic treatments with antiinflammatory drugs seeking reduce or annul the adverse effects ofgastric ulceration from the discovery that aminoacids associated to antiinflammatory administered orally reduce the extension of the gastriclesion, where taurine present an important role in this mechanism,particularly regarding to its participation in the pro inflammatorycytokines regulation process.

SUMMARY OF THE INVENTION

The present invention has as its objective to reduce the side andadverse effects of the non-steroidal anti inflammatory (NSAI) drugs byproviding novel compounds based in taurine-derived ones. Morespecifically, the invention has as its foundation the introduction of anamidic bond between the molecules of NSAIs and taurine, resulting innovel compounds of the invention which adjuvant activity results bynitric oxide production inhibition induced in the inflammatory processby specific enzymes present in the macrophages and neutrophyls(inducible nitric oxide synthase—iNOS) as well as by cyclooxygenaseinhibition and probably by the active principles slow in vivo releaseleading to a toxicity control of NSAI drugs with the maintenance oftheir anti inflammatory activity.

A first embodiment of the present invention is regarding thetaurine-derived compounds, which taurine is directly linked by means ofan amide bond or through an spacing group to a selected compound from agroup of non-steroidal anti inflammatory compound, calledtaurine-derived and presenting Formula (I):

which R means the component with non-steroidal anti inflammatoryactivity.

In a second embodiment, the present invention provides an obtaintionprocess of novel Formula (I) compounds, its salts, solvates, hydrates,enantiomers, diasteroisomers and polymorphs, comprising the taurinereaction with a compound belonging to the group of non-steroidal antiinflammatory (NSAI) drugs, in the presence of an appropriate catalyzer,in order to obtain a taurine-derived compound through direct bond or bythe means of an spacing group of taurine to NSAI.

In a third embodiment, the present invention is regarding thepharmaceutical compositions comprising: (a) a taurine-derived compoundwith anti inflammatory activity from the non-steroidal type, (b)optionally, an appropriate active principle for treating a medicalcondition involving an inflammatory disturbance and (c) apharmaceutical-acceptable vehicle.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows a comparative assay of the anti inflammatory activity perrat's paw using taurine, naproxen and its derived compound (Compound 63,embodiment of the invention corresponding to Example 2).

FIG. 2 shows a comparative assay of the anti inflammatory activity perrat's paw using taurine, indometacin and its derived compound (Compound64, embodiment of the invention corresponding to Example 3).

FIG. 3 shows a comparative assay of the anti inflammatory activity perrat's paw using taurine, ibuprophen and its derived compound (Compound27, embodiment of the invention corresponding to Example 1).

FIG. 4 graphically demonstrates the weight profile, in grams, of theorgans: kidneys, heart and liver regarding the body weight of eachanimal, given in percentage, when the ibuprophen-derived compound isadministered after the toxicity assay (Compound 27, embodiment of theinvention corresponding to Example 1).

FIG. 5 graphically shows the organ weight differences when theibuprophen-derived compound is administered: In A=liver; and B, thesuperior slope equals to kidneys and the inferior one to the heart.

FIG. 6 graphically represents the weight profile, in grams, of theorgans: kidneys, heart and liver related to the body weight of eachanimal, given in percentage, when the naproxen-derived is administeredafter the toxicity assay (Compound 63, embodiment of the inventioncorresponding to Example 2).

FIG. 7 graphically shows the organ weight differences when thenaproxen-derived compound is administered: In A=liver; and B, thesuperior slope equals to kidneys and the inferior one to the heart.

FIG. 8 graphically represents the weight profile, in grams, of theorgans: kidneys, heart and liver related to the body weight of eachanimal, given in percentage, when the indometacin-derived isadministered after the toxicity assay (Compound 64, embodiment of theinvention corresponding to Example 3).

FIG. 9 graphically shows the organ weight differences when theindometacin-derived compound is administered: In A=liver; and B, thesuperior slope equals to kidneys and the inferior one to the heart.

FIG. 10 graphically shows the gastrotoxicity tests that have beenconducted: (i) with the NSAI drugs ibuprophen, naproxen and indometacin,(ii) with the equimolar physical mixture of taurine with these NSAIdrugs and (iii) with the compounds 63 (taurine-ibuprophen), 27(taurine-naproxen) and 64 (taurine-indometacin) of the invention.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the invention are derived from taurine, obtained fromde formation of amidic bonds with non-steroidal anti inflammatory (NSAI)drugs, directly as well as through a provided spacing agent.

Following, some definitions are provided, in order to facilitate thecomprehension of the present invention.

-   -   Taurine—2-aminoethanesulfonic acid

non-essential aminoacid which is one of the most abundant aminoacids inthe human body.

-   -   Amidic bond—chemical bond of the —NHCOY-type between the        component with non-steroidal anti inflammatory activity (NSAI)        (drug) and taurine (transporter).    -   Non-steroidal anti inflammatory (NSAI) drugs—they are substances        with anti inflammatory, analgesic and antipyretic effect. The        NSAI drugs act in the organism blocking the prostaglandins        synthesis and include compounds as: salycilates, pyrazolons and        analogs, derived indoleacetics, derived arilacetics, derived        arylpropionics, oxycams and phenamates.    -   Spacing agent—intermediate chemical group that establishes the        bond between the drug and the transporter. In the chemical        release of the drug, the use of an spacing agent allows better        and higher access of the enzyme; this way, the release of the        active portion is facilitated which consists in the major factor        in the manifestation of the biological activity.    -   Taurine-derived compounds—includes the isomers, enantiomers,        analogs and prodrugs resultant from the bond of taurine with a        selected compound from the group of NSAI drugs through a direct        amidic bond or by means of an spacing agent.

The compounds of the present invention are compounds represented by thegeneral Formula (I):

where the taurine component:

is linked, directly or through an spacing agent, to NSAI drug, formingand amidic bond of the —NHCOY-type, which the —COY group correspond tothe R substituent of the general Formula (I).

The NSAI components of the invention can be any component belonging tothe non-steroidal anti inflammatory group. Preferentially, the NSAIcomponent out of the compounds of the invention can be any R substituentas defined in Table 1.

TABLE 1 Preferred Formula (I) Compounds R Substituent Formula (I)Compound

Derived from 2-[2-(2,6- Compound 1: 2-{2-[2-(2,6- dichlorophenylamino)phenyl] dichlorophenylamino) phenyl] acetic acid acetamide}ethanesulfonic acid

derived from 2-[(2,6-dichloro- Compound 2: 2-{[(2,6-dichloro-3-3-methylphenyl) amino] benzoic methylphenyl) aminobenzoil] acid amide}ethanesulfonic acid

derived from 2-{[3- Compound 3: 2-{[3-(trifluoromethyl)(trifluoromethyl) phenyl] amino} nicotinoyl] amide} phenyl] amino}nicotinic acid ethanesulfonic acid

derived from 2-[(2,3- Compound 4: 2-{[(2,3- dimethylphenyl) amino]benzoic dimethylphenyl) amino]benzoyl] acid amide} ethanesulfonic acid

derived from 2-[(2,4- Compound 5: 2-{[(2,4- dichlorophenoxy) phenyl]dichlorophenoxy) phenyl] acetyl] acetic acid amide} ethanesulfonic acid

derived from 2-[(3-chloro-2- Compound 6: 2-{[(3-chloro-2- methylphenyl)amino] benzoic methylphenyl)amino] benzoyl] acid amide} ethanesulfonicacid

derived from 2-[(2,3- Compound 7: 2-{[(2,3- dimethylphenyl) amino]benzoic dimethylphenyl) amino]benzoyl] acid amide} ethanesulfonic acid

derived from 2-[(1,2-diphenyl- Compound 8: 2-{[(1,2-diphenyl- hydrazino)carbonyl] hexanoic hydrazino) carbonyl] hexanoyl] acid amide}ethanesulfonic acid

derived from 4-[(4-butyl-3,5- Compound 9: 4-{[(4-butyl-3,5-dioxo-1,2-diphenylpyrazolidin- dioxo-1,2-diphenylpyrazolidin-4- 4-yl)methoxy]-4-oxobutanoic yl) methoxy]-4-oxobutanoyl] acid amide}ethanesulfonic acid

derived from (1,3,4-triphenyl- Compound 10:{[(1,3,4-triphenyl-1H-pyrazol- 1H-pyrazol-5-yl)acetic acid 5-yl)acetyl]amide} ethanesulfonic acid

derived from [3-(4- Compound 11: {[[3-(4-chlorophenyl)-1-chlorophenyl)-1-phenyl-1H- phenyl-1H-pyrazol-4- pyrazol-4-yl] aceticacid yl] acetyl] amide} ethanesulfonic acid

derived from [(1-benzyl-1H- Compound 12:{[(1-benzyl-1H-indazol-3-yl)oxy] indazol-3-yl)oxy] acetic acid acetyl]amide} ethanesulfonic acid

derived from [4-(4- Compound 13: {[[4-(4- chlorophenyl)-2-phenyl-1,3-chlorophenyl)-2-phenyl-1,3-thiazol-5-yl] thiazol-5-yl] acetic acidacetyl] amide} ethanesulfonic acid

derived from [2-(4- Compound 14: {[[2-(4- chlorophenyl)-1,3-thiazol-4-chlorophenyl)-1,3-thiazol-4-yl] acetyl] yl] acetic acid amide}ethanesulfonic acid

derived from 3-(4,5-diphenyl- Compound 15: 3-{[(4,5-diphenyl-1,3-oxazol-1,3-oxazol-2-yl)propanoic acid 2-yl)propanoyl] amide} ethanesulfonicacid

derived from [1-(4- Compound 16: ([[1-(4-chlorophenyl)-2,5-chlorophenyl)-2,5-dimethyl-1H- dimethyl-1H-pyrol-3-yl] acetyl]pyrol-3-yl] acetic acid amide} ethanesulfonic acid

derived from 2-amino-6-benzyl- Compound 17: 2-{[amino-6-benzyl-4,5,6,7-4,5,6,7-tetrahydrothieno[2,3- tetrahydrothieno[2,3-c]pyridine-3-carboxylyl] c] pyridine-3-carboxylic acid amide}ethanesulfonic acid

derived from [2- Compound 18: {[[2- (aminocarbonyl) phenoxy](aminocarbonyl) phenoxy] acetyl] acetic acid amide} ethanesulfonic acid

derived from 2,5- Compound 19: [(2,5-dihydroxybenzoyl) dihydroxybenzoicacid amide] ethanesulfonic acid

derived from 2-(sulphooxy) Compound 20: {[2-(sulphooxy) benzoic acidbenzoyl] amide} ethanesulfonic acid

derived from 2-[(2- Compound 21: 2-{[(2- hydroxybenzoyl)oxy] benzoichydroxybenzoyl)oxy] benzoyl] acid amide} ethanesulfonic acid

derived from 2-[(2- Compound 22: 2-{[(2- phenylethyl)amino] benzoicphenylethyl)amino] benzoyl] acid amide} ethanesulfonic acid

derived from 5-[(2-phenyl-4,5- Compound 23:5-{[(2-phenyl-4,5-dihydro-3H- dihydro-3H-benzo[e]-1H-indole-benzo[e]-1H-indole-2-(2-hydroxybenzoyl) 2-(2-hydroxybenzoic acid)amide]} ethanesulfonic acid

derived from 2′,4′-difluoro-4- Compound 24: acid [(2′,4′-difluoro-4-hydroxy-1,1′-diphenyl-3- hydroxy-1,1′-diphenyl-3-carboxylyl) carboxylicacid amide] ethanesulfonic

derived from [2- Compound 25: {[[2- (aminocarbonyl) phenoxy](aminocarbonyl) phenoxy] acetyl] acetic acid amide} ethanesulfonic acid

derived from 2-(4- Compound 26: 2-{[2-(4-isobuthylphenyl)isobuthylphenyl) butanoic acid butanoyl] amide} ethanesulfonic acid

derived from 2-(4- Compound 27: [2-(4- isobuthylphenyl) propanoicisobuthylphenyl) propanoyl] acid amide ethanesulfonic acid

derived from 2-[4-(thien-2-yl- Compound 28: {2-[4-(thien-2-yl- carbonyl)phenyl] propanoic carbonyl) phenyl] propanoyl} acid amide ethanesulfonicacid

derived from 2-(3- Compound 29: {2-(3-phenoxyphenyl) phenoxyphenyl)propanoic acid propanoyl} amide ethanesulfonic acid

derived from chloro (3-chloro- Compound 30: [chloro (3-chloro-4-cyclo-hexylphenyl) acetic 4-cyclo-hexylphenyl) acetyl] acid amideethanesulfonic acid

derived from 4-(3-chloro-4- Compound 31: [4-(3-chloro-4-cyclo-cyclo-hexyl phenyl)-4- hexyl phenyl)-4-oxobutanoyl] amide oxobutanoicacid ethanesulfonic acid

derived from 6-chloro-5-cyclo- Compound 32:(6-chloro-5-cyclo-hexylindane-l- hexylindane-1-carboxilic acid carboxyl)amide ethanesulfonic acid

derived from 2-{4-[(2- Compound 33: 2-{4-[(2-methylprop-2-methylprop-2-enil) amino] enil) amino] phenyl-propanoyl}phenyl}propanoic acid amide ethanesulfonic acid

derived from 2-(5- Compound 34: [2-(5-benzoylthien- benzoylthien-2-yl)propanoic 2-yl) propanoyl] amide acid ethanesulfonic acid

derived from 5-benzoyl-2,3- Compound 35: (5-benzoyl-2,3-dihydro-1H-pyrolizine-1- dihydro-1H-pyrolizine-1- carboxylic acidcarboxyl) amide ethanesulfonic acid

derived from 2-[2-(4- Compound 36: {2-[2-(4-fluorophenyl)-fluorophenyl)-1,3-benzoxazol- 1,3-benzoxazol-5-yl] propanoyl} 5-yl]propanoic acid amide ethanesulfonic acid

derived from 2-[2-(4- Compound 37: {2-[2-(4-chlorophenyl)-chlorophenyl)-1,3-benzoxazol- 1,3-benzoxazol-5-yl] propanoyl} 5-yl]propanoic acid amide ethanesulfonic acid

derived from 2-(3- Compound 38: [2-(3-benzoylphenyl) benzoylphenyl)propanoic acid propanoyl] amide ethanesulfonic acid

derived from 2-(4-imidazo[1,2- Compound 39: [2-(4-imidazo[1,2-a]pyridin-2-yl phenyl) a]pyridin-2-yl phenyl) propanoyl] propanoic acidamide ethanesulfonic acid

derived from [1-methyl-5-(4- Compound 40: {[1-methyl-5-(4-methylbenzoyl)-1H-pyrol-2-yl] methylbenzoyl)-1H-pyrol-2-yl] acetic acidacetyl} amide ethanesulfonic acid

derived from [5-(4- Compound 41: {[5-(4-chlorobenzoyl)-chlorobenzoyl)-1,4-dimethyl-1H- 1,4-dimethyl-1H-pyrol-2-yl] pyrol-2-yl]acetic acid acetyl} amide ethanesulfonic acid

derived from 2-(5- Compound 42: [2-(5-benzoylthien- benzoylthien-2-yl)propanoic 2-yl) propanoyl] amide acid ethanesulfonic acid

derived from 2-[3-chloro-4- Compound 43: {2-[3-chloro-4-(2,5-(2,5-dihydro-1H-pyrol-1- dihydro-1H-pyrol-1-yl)phenyl] propanoyl}yl)phenyl] propanoic acid amide ethanesulfonic acid

derived from 5-benzoyl-2,3- Compound 44: (5-benzoyl-2,3-dihydro-1H-pyrolizine-1- dihydro-1H-pyrolizine-1- carboxylic acidcarboxyl) amide ethanesulfonic acid

derived from (11-oxo-6,11- Compound 45: [(11-oxo-6,11- dihydrodibenzo[b,e]oxepin-2- dihydrodi benzo[b,e]oxepin-2- yl)acetic acidyl)acetyl] amide ethanesulfonic acid

derived from 2-(2-fluoro-1,1′- Compound 46:[2-(2-fluoro-1,1′-diphenyl-4- diphenyl-4-yl) propanoic acid yl)propanoyl] amide ethanesulfonic acid

derived from [4-(allyloxy)-3- Compound 47:{[4-(allyloxy)-3-chlorophenyl] chlorophenyl] acetic acid acetyl} amideethanesulfonic acid

derived from 2-[2-(4- Compound 48: {2-[2-(4-chlorophenyl)-chlorophenyl)-1,3-benzoxazol- 1,3-benzoxazol-5-yl] propanoyl) 5-yl]propanoic acid amide ethanesulfonic acid

derived from 2-[4-(1-oxo-1,3- Compound 49: {2-[4-(1-oxo-1,3-dihydro-dihydro-2H-isoindole-2- 2H-isoindole-2-yl)phenyl] propanoyl} yl)phenyl]propanoic acid amide ethanesulfonic acid

derived from 6-chloro-5-cyclo- Compound 50:(6-chloro-5-cyclo-hexylindane- hexylindane-1-carboxylic acid 1-carboxyl)amide ethanesulfonic acid

derived from 2-[4-(2,5- Compound 51: {2-[4-(2,5- dihydrothien-2-yldihydrothien-2-yl carbonyl) phenyl] propanoic carbonyl)phenyl]propanoyl} acid amide ethanesulfonic acid

derived from 2-(5- Compound 52: [2-(5-benzoylthien- benzoylthien-2-yl)propanoic 2-yl) propanoyl] amide acid ethanesulfonic acid

derived from [1-methyl-5-(4- Compound 53: {[[1-methyl-5-(4-methylbenzoyl)-1H-pyrol-2-yl] methylbenzoyl)-1H-pyrol-2-yl] acetic acidacetyl] amide} ethanesulfonic acid

derived from [1-(4- Compound 54: {[[1-(4-chlorophenyl)-chlorophenyl)-2,5-dimethyl-1H- 2,5-dimethyl-1H-pyrol-3-yl] pyrol-3-yl]acetic acid acetyl] amide} ethanesulfonic acid

derived from [1-(4- Compound 55: {[[1-(4-chlorophenyl)-chlorophenyl)-2,5-dimethyl-1H- 2,5-dimethyl-1H-pyrol-3-yl] pyrol-3-yl]acetic acid acetyl] amide} ethanesulfonic acid

derived from 2-(5H- Compound 56: 2-{[(5H-chromene[2,3-chromene[2,3-b]pyridin-7-yl) b]pyridin-7-yl) propanoyl] amide} propanoicacid ethanesulfonic acid

derived from 4-(1,1′-biphenyl- Compound 57: 4-{[(1,1′-biphenyl-4-yl)-4-4-yl)-4-oxobutanoic acid oxobutanoyl] amide} ethanesulfonic acid

derived from 1,1′-biphenyl-4- Compound 58: [(1,1′-biphenyl-4- yl aceticacid yl acetyl) amide] ethanesulfonic acid

derived from 3-(4,5-diphenyl- Compound 59:3-{[(4,5-diphenyl-1,3-oxazol-2- 1,3-oxazol-2-yl)propanoic acidyl)propanoyl] amide} ethanesulfonic acid

derived from 2-[4-(1-oxo-1,3- Compound 60: 2-{[[4-(1-oxo-1,3-dihydro-2H-dihydro-2H-isoindole-2-yl) isoindole-2-yl) phenyl] propanoyl] phenyl]propanoic acid amide} ethanesulfonic acid

derived from 4-[(4- Compound 61: 4-{[[(4-chlorophenyl)-2-chlorophenyl)-2-phenyl-1,3- phenyl-1,3-thiazol-5-yl] acetyl]thiazol-5-yl] acetic acid amide} ethanesulfonic acid

derived from 4-[(4- Compound 62: 4-{[[(4- chlorophenyl)-1,3-thiazol-5-chlorophenyl)-1,3-thiazol-5-yl] yl] acetic acid acetyl] amide}ethanesulfonic acid

derived from 2-(6-methoxy-2- Compound 63: 2-{[2-(6-methoxy-2-naphthyl)naphthyl) propanoic acid propanoyl] amide} ethanesulfonic acid

derived from [1-(4- Compound 64: [1-(4-chlorobenzoyl)-5-chlorobenzoyl)-5-methoxy-2- methoxy-2-methyl-1H-indole-3-yl]acetyl]methyl-1H-indole-3-yl]acetic amide} ethanesulfonic acid acid

derived from {5-methoxy-2- Compound 65: {[(5-methoxy-2-methyl-1-[(2E)-3-phenylprop-2- methyl-1-[(2E)-3-phenylprop-2-enoyl]-1H-indole-3-yl} acetic enoyl]-1H-indole-3-yl) acetyl] acid amide}ethanesulfonic acid

derived from ({[1-(4- Compound 66: {[(5-methoxy-2-chlorobenzoyl)-5-methoxy-2- methyl-1-[(2E)-3-phenylprop-2-methyl-1H-indole-3-yl]acetyl} enoyl]-1H-indole-3-yl) acetyl] oxy) aceticacid amide} ethanesulfonic acid

derived from (1,8-diethyl- Compound 67: {[(1,8-diethyl-1,3,4,9-1,3,4,9-tetrahydrofuran[3,4- tetrahydrofuran[3,4-b]indole-1-yl)b]indole-1-yl) acetic acid acetyl] amide} ethanesulfonic acid

derived from {((1E)-5-fluoro- Compound 68: {[((1E)-5-fluoro-2-2-methyl-1-[4- methyl-1-[4-(methylsulphonyl) (methylsulphonyl)benzylidene]-1H-inden-3-yl) benzylidene]-1H-inden-3-yl) acetyl] amide}ethanesulfonic acetic acid acid

derived from 2-(6-chloro-9H- Compound 69: 2-{[(6-chloro-9H-carbazol-carbazol-2-yl) propanoic acid 2-yl) propanoyl] amide} ethanesulfonicacid

The compounds of the present invention present anti inflammatoryactivity of the non-steroidal type, antipyretic, analgesic and plateletanti aggregant activity and are useful as adjuvant in the treatment ofinflammatory processes such as rheumatoid arthritis, ulcerative colitis,Chron's disease and other inflammatory diseases, such as for example,neurodegenerative diseases such as Alzheimer's disease, with a minimumpotential of gastric irritation.

Particularly regarding ulcerative colitis and Chron's disease, thecompounds of the present invention provide gastrintestinal antiinflammatory and antioxidant activity.

Taking into consideration that taurine is found in high concentrationsin young brains and lowers with the age, and knowing that theinflammatory process is one of the causes of amyloid plate formation inAlzheimer disease, the compounds of the present invention can be usefulfor the prevention/treatment of this disease, once taurine itselfincreases the learning capacity in aged animals (El Idrissi, A. Taurineimproves learning and retention in aged mice. Neuroscience Letters, 2008DOI 10.1016/J.neulet 2008.02.070).

The compounds of the present invention are obtained through a processthat comprises the reaction of taurine with a substance presentingnon-steroidal anti inflammatory (NSAI) activity, in the presence of anappropriate catalyzer, in order to enable the formation of an directamide bond or by the means an intermediate spacing agent between taurineand the NSAI component.

The substance presenting non-steroidal anti inflammatory activity can beselected from the group consisting of the following NSAI drugs:salycilates, pyrazolons and analogs, derived indoleacetics, derivedarilacetics, derived arylpropionics, oxycams and phenamates. The NSAIfrom the group of salycilates can be chosen from: lysine clonixinate,benorylate, diflunisal, etersalate and salsalate. The NSAI from thegroup of pyrazolons and analogs can be chosen from: phenylbutazone,oxyphenbutazone, aminophenazone, bumadizone, pheprazone, niphenazone andsuxibuzone. The NSAI from the group of the derived indoleacetics can bechosen from: acematacin, glucametacin, indometacin, proglumetacin,oxametacin, sulindac and tolmetin. The NSAI from the group of derivedarilacetics can be chosen from: aceclophenac, diclophenac, fentiazac andnabumetone. The NSAI from the group of the derived arylpropionics can bechosen from: butibuphen, phenbuphen, flurbiprophen, ibuprophen,ibuproxam, ketoprophen, naproxen, loxoprofen, panoprofen, oxaprozin andthiaprophen. The NSAI from the group of oxycams can be chosen from:droxicam, meloxicam, pyroxicam and tenoxicam. The NSAI from the group ofphenamates can be chosen from: meclophenamic acid, mephenamic acid,tolphenamic acid and niflumic acid.

Preferentially, the process of the present invention for obtaintion ofthe compounds of the invention is of the latentiation type, in which achemical modification in a biologically active compound is performed inorder to form a novel compound, which will release in vivo the compoundor original drug. Latentiation of a drug is synonym of prodrug planning.

However, it is worth noting that mechanism of action of the compounds ofthe present invention is not completely elucidated and, then, it is notpossible to assure that the cited compounds correspond to prodrugs orare novel chemical entities. In other words, the compounds of thepresent invention can also present activity without the prodrug in vivobreakdown; therefore, it can present activity per se. In fact, whencomparing the gastroprotection assays, provided below in the presentdescriptive report, performed with the compounds of the invention andtheir physical mixtures with known non-specific and specific NSAIs (forCOX-2 inhibition), it was surprisingly observed that the compounds ofthe present invention did not lead to gastric lesion, have kept the antiinflammatory potency and presented superior safety according to thestandards (based on the original NSAIs), as shown in FIGS. 1 to 4.

More precisely, the process of the present invention comprises thereaction of a selected NSAI selected from the anti inflammatorysubstances as defined herein (original drug) with the ethanesulfonicaminoacid (taurine), in the presence of an appropriate catalyzer, inorganic solvent media.

The catalyzer used in the process of the present invention can be anycatalyzer used commonly in latentiation processes. It can be cited aspreferred ones the following catalyzers: diethylcyanophosphonate,1-hydroxybenzotriazol, carboiimides, triethyamine, imidazole, pyrazole,1,2,4-triazole, 4-dimethylaminopyridine, pyridine and similar.

More preferentially, according to the process of the present invention,DEPC (diethylcyanophosphonate).

The process of the present invention is performed, preferentially, inthe presence of an organic solvent. The following solvents arepreferred: acetone, tetrahydrofuran (THF) or dimethylformamide (DMF).

The reaction can be performed at room temperature, in highly basic mediafor up to 2 hours. In a preferred way, the precipitated formed ispurified by any technique known from the state of technique forobtaining the compound of the invention according to the requiredspecifications by the current legislation for use in the preparation ofdrugs for human or animal use, such as C₁₅H₂₃NO₄S (embodimentcorresponding to Example 1) C₁₆H₁₉NO₅S (embodiment corresponding toExample 2); C₂₁H₂₁ClN₂O₆S (embodiment corresponding to Example 3).

The compounds of the invention are utilizable in the preparation of antiinflammatory drugs in the form of solid, liquid, solid-liquid orsolid-gaseous suspensions (for example, aerosols) pharmaceuticalcompositions, creams, gels, adhesive patchesandother pharmaceuticalforms of anti inflammatory drugs of systemic use or adequate localapplication. The preferred pharmaceutical forms are solid, aerosols,creams and gels containing the compounds of the present invention. Assolid pharmaceutical forms, it can be cited tablets, capsules, pills andsimilar. The solid forms can also be of rapid release, controlled orlong lasting type. As long as the taurine derived compounds of thepresent invention are easily soluble, the injectable forms are alsopreferred, according to the invention.

In the case of injectable forms, the taurine derived compounds of thepresent invention can be administered by parentheral means, includingthe endovenous (or intravenous), the muscular, the subepidermal andintradermic. For subepidermal or intravenous administration, thepharmaceutical composition of the invention can be in the form ofsolution, suspension or emulsion, including substances typically used insuch preparations, such as solubilizers, emulsifiers or other additives.The appropriate solvents are water, physiological saline solution oralcohols, for example, ethanol, propanol, glycerol, and, additionally,sugar solutions, such as glucose or mannitol, or mixtures of so calledsolvents.

The pharmaceutical compositions of the invention can also be in the formof aerosol, such as solutions, suspensions or emulsions of the activeingredient in a pharmaceutically acceptable solvent, such as ethanol orwater or their mixtures. It can also be present additives, such astensoactives, emulsifiers, stabilizers and propellants.

The pharmaceutical compositions of the present invention comprise: (a)at least one of the general formula (I) compounds, (b) optionally, atleast one appropriate active principle for the treatment of a medicalcondition involving an inflammatory disturbance and (c) apharmaceutically acceptable vehicle or excipient.

The term pharmaceutically acceptable vehicle or excipient with theintention of meaning any substance or substances that are inert used asvehicle or diluents for any of the active principles of the compositionof the present invention.

In the case of the pharmaceutical form of the composition of theinvention be a tablet, it can include one or more vehicles, excipientsand/or additives selected from the group consisting of diluents,desintegrants, ligands, dyes and flavorizant agents. The diluent can beone or more among calcium carbonate, dibasic calcium phosphate, tribasiccalcium phosphate, calcium sulphate, microcrystalline cellulose,pulverulent cellulose, dextrats, dextrins, dextrose excipients,fructose, china clay, lactitol, lactose, mannitol, sorbitol, sucrose,compressible sugar and confectioner's sugar, and, in particular, can belactose. The ligand can be one or more among methylcellulose,hydroxypropylcellulose, hydroxypropyl methylcellulose,polyvinylpyrrolidone, gelatin, gum arabic, ethylcellulose, polyvinylicalcohol, pululane, pre-gelatinized amide, agar, tragacanth, alginicacid-derived and propylene glycol-derived, and alginate, and, inparticular, can be polyvinylpyrrolidone. The desintegrant can be one ormore among low molecular weight substituted hydroxypropylcellulose,carboxymethyl cellulose, carboxymethyl calcium cellulose, carboxymethylsodium cellulose, croscarmellose sodium, amide, crystalline cellulose,hydroxypropyl amide, and amide partially pre-gelatinized.

The pharmaceutical compositions of the present invention can be preparedby processes known from the state of the technique.

It has to be understood that the examples and embodiments describedherein are solely for illustrative purpose and that variousmodifications and changes, in the light of themselves, will besuggestive to the specialists in the technique and must be included inthe spirit and scope of this description and the scope of the claimsthat follow it. All the publications, patents and patent applicationscited herein are incorporated by reference in their entirety and for allpurposes.

The compounds of the invention are preferentially prepared through alatentiation process with the use of a appropriate catalyzer. Following,a general procedure is provided that can be employed for obtainingprodrugs comprising a first component corresponding to a NSAI and asecond component corresponding to taurine, in which the first and secondcomponents are directly linked or by the means of an spacing agent,through an amidic bond. Therefore, the general proceeding, described asfollow, can be used to prepare any one of the 70 preferred compounds ofthe invention presented in Table 1.

General Procedure for Obtaining Amides (Taurine Derived) According tothe Present Invention

An acid compound equivalent (NSAI) is solubilized in DMF previouslydried out under molecular screen cleaner. Sequentially, an ice bath, 1,2diethylcyanophosphonate (DEPC) equivalent, 2 taurine equivalent and 11previously dried out under molecular screen cleaner triethylamineequivalent are added. The reaction is kept for 2 hours shaking at roomtemperature.

At end of the reaction, the base excess is removed through nitrogenpull-down, and the remaining solvent is eliminated through evaporationat reduced pressure. The obtained residue is added, in small portions,to a saturated aqueous cold NaHCO₃ solution. The formed precipitated iscollected by filtration, washed with a small portion of cold water anddried out under phosphorus pentoxide. The obtained dry mass is grindedunder THF, with the solid residue being filtrated and dried out.

Example 1 [2-(4-isobuthylphenyl)propanoyl]amide ethanesulfonic acid(Compound 27) Synthesis (Compound Derived from Ibuprophen and Taurine)

One gram of ibuprophen is solubilized in DMF previously dried out undermolecular screen cleaner. Sequentially, an ice bath, 0.9 mL ofdiethylcyanophosphonate (DEPC), 1.212 g of taurine and 7.8 mL ofpreviously dried out under molecular screen cleaner triethylamine areadded. The reaction is kept for 2 hours shaking at room temperature.

At end of the reaction, the base excess is removed through nitrogenpull-down, and the remaining solvent is eliminated through evaporationat reduced pressure. The obtained residue is added, in small portions,to a saturated aqueous cold NaHCO₃ solution. The formed precipitated iscollected by filtration, washed with a small portion of cold water anddried out under phosphorus pentoxide. The obtained dry mass is grindedunder THF, with the solid residue being filtrated and dried out andcalculated yield of around 90% (analyzed by high performance liquidchromatography—HPLC)

The study of structural confirmation of the purified product led to theresult of Table 2.

TABLE 2 Structural characterization of the resulting Compound from thereaction between taurine and ibuprophen (Compound 27)

  [2-(4-isobuthylphenyl) propanoyl] amide ethanesulfonic acid Group 1H13C HMBC 1 — 135.58 — 2 2H; 7.17 d 129.42 45.45; 127.69; 139.60 (J = 8.1Hz) 3 2H; 7.05 d 127.69 44.70; 45.45; 129.42; 139.60 (J = 8.1 Hz) 4 —139.60 — —CH— (A) 1H; 3.46 q 45.45 19.12; 127.69; 139.60; 173.60 (J =7.1 Hz) —CH— (B) 1H; 1.79 hep 30.05 22.80; 44.70; 139.60 (J = 6.9 Hz)—CH3 (A) 3H; 1.28 d 19.12 45.45; 139.60; 173.60 (J = 7.1 Hz) —CH3 (B)6H; 0.84 d 22.80 30.05; 44.70 (J = 6.9 Hz) —CH2—Ar 2H; 2.39 d 44.7022.80; 30.05; 129.42; 139.60 (J = 7.3) C═O — 173.60 — NH 1H; 7.81 t —36.60; 173.60 (J = 5.3 Hz) NH—CH2— 2H: 3.26 36.60 50.98; 173.60—CH2—SO3Na 2H; 2.49 50.98 36.60

Example 2 2-{[2-(6-methoxy-2-naphthyl) propanoyl]amide}ethanesulfonicacid (Compound 63) Synthesis

One gram of naproxen is solubilized in DMF previously dried out undermolecular screen cleaner. Sequentially, an ice bath, 0.8 mL ofdiethylcyanophosphonate (DEPC), 1.085 g of taurine and 7.0 mL ofpreviously dried out under molecular screen cleaner triethylamine areadded. The reaction is kept for 2 hours shaking at room temperature.

At end of the reaction, the base excess is removed through nitrogenpull-down, and the remaining solvent is eliminated through evaporationat reduced pressure. The obtained residue is added, in small portions,to a saturated aqueous cold NaHCO₃ solution. The formed precipitated iscollected by filtration, washed with a small portion of cold water anddried out under phosphorus pentoxide. The obtained dry mass is grindedunder THF, with the solid residue being filtrated and dried out andcalculated yield of around 90% (analyzed by HPLC).

After the purification of the product, the study of structuralconfirmation led to the result of Table 3.

TABLE 3 Structural characterization of the resulting Compound from thereaction between taurine and naproxen (Compound 63)

  2-{[2-(6-methoxy-2-naphthyl) propanoyl] amide} ethanesulfonic acidGroup 1H 13C HMBC  1 — 157.75 —  2 1H; 7.12 dd (J = 9.0 and 1.7 Hz)119.1 106.46; 129.31; 157.75  3 1H; 7.76 d (J = 9.0 Hz) 130.23 125.88;129.31; 133.85; 157.75  4 1H; 7.68 sl 125.88  45.8; 127.31; 130.23;133.85  5 — 138.28 —  6 1H; 7.40 d (J = 8.5 Hz) 127.31  45.8; 106.46;125.88; 133.85  7 1H; 7.72 d (J = 8.5 Hz) 128.8 129.31; 138.28  8 1H;7.25 sl 106.46 119.1; 128.8; 157.75  9 — 129.31 — 10 — 133.85 — CH3—O—3H; 3.84 s 65.36 106.46; 157.75; CH3— 3H; 1.38 d (J = 6.95 Hz) 18.70 45.8; 138.28; 173.70 CH— 1H; 3.64 q (J = 7.0 Hz) 45.8  18.70; 125.88;133.85; 138.28; 173.70 C═O — 173.70 — NH 1H; 7.88 t (J = 5.5 Hz) — 36.3; 173.70 NH—CH2— 2H; 3.26 36.3  51.05; 173.70 —CH2—SO3Na 2H; 2.4951.05  36.3

Example 3[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-yl]acetyl]amide}ethanesulfonicacid (Compound 64) Synthesis

One gram of indometacin is solubilized in DMF previously dried out undermolecular screen cleaner. Sequentially, an ice bath, 0.5 mL ofdiethylcyanophosphonate (DEPC), 0.700 g of taurine and 4.5 mL ofpreviously dried out under molecular screen cleaner triethylamine areadded. The reaction is kept for 2 hours shaking at room temperature.

At end of the reaction, the base excess is removed through nitrogenpull-down, and the remaining solvent is eliminated through evaporationat reduced pressure. The obtained residue is added, in small portions,to a saturated aqueous cold NaHCO₃ solution. The formed precipitated iscollected by filtration, washed with a small portion of cold water anddried out under phosphorus pentoxide. The obtained dry mass is grindedunder THF, with the solid residue being filtrated and dried out andcalculated yield of around 90% (analyzed by HPLC).

After the purification of the product, the study of structuralconfirmation led to the result of Table 4.

TABLE 4 Structural characterization of the resulting Compound from thereaction between taurine and indometacin (Compound 64)

  [1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-yl]acetyl]amide}ethanesulfonic acid Group 1H 13C HMBC  1 — 129.5 —  2 2H; 7.75 d (J =8.2 Hz) 134.95 131.95; 138.23; 168.7  3 2H; 7.62 d (J = 8.2 Hz) 131.95129.5; 134.95; 138.23; 168.7  4 — 138.23 —  5 — 130.9 —  6 1H; 7.03 d (J= 9.0 Hz) 119.32 101.7; 130.9; 156.32  7 2H; 6.70 dd (J = 9.0 and 2.3Hz) 102.16 102.16; 130.9; 156.32  8 — 156.32 —  9 1H; 7.06 d (J = 2.3Hz) 101.7 114.7; 130.9; 156.32 10 — 114.7 — 11 — 129.5 — 12 — 136.1 —C═O — 168.7 — —CH3 3H; 2.15 s 14.0 114.7; 119.32; 136.1; 169.35 —O—CH33H; 3.76 s 65.2 156.32 —CH2—C═O 3.48 s * 55.9 114.7; 130.9; 136.1;169.35 —C═ONH — 169.35 — NH 1H; 7.88 t (J = 5.2 Hz) — 169.35; 35.9NH—CH2— 2H; 3.32 t (J = 5.4 Hz) 35.9 169.35 —CH2—SO3Na 2H; 2.53 t (J =6.65 Hz) 51.03  35.9

Example 4 Biological Assay

Since taurine has the ability of inhibiting iNOS present in themacrophages of the inflammatory processes, the objective of this studywas of verifying if the binding of the anti inflammatory component ofthe group of NSAIs to taurine would cause alteration in this activity,in other words, if the capacity of taurine to inhibit iNOS would bereduced, therefore abolishing its anti inflammatory activity.

The assay used the maximum production of nitric oxide (macrophagesstimulated with LPS), by indirect method of nitrite (NO₂ ⁻) detection aspositive control, and in the negative control aminoguanidine, a falseenzymatic substrate, was used, leading to the observation of totalinhibition of nitric oxide production.

The results have demonstrated that the non-steroidal anti inflammatory(NSAI) drugs do not present NOS inhibition activity, once the NOproduction was the same as observed in the positive control (LPS).

The results obtained with the use of the compounds of the presentinvention have demonstrated that they were active in the NO production,similar to taurine, suggesting that the binding of NSAIs to taurine didnot modify this activity.

These results suggest that the taurine derived compounds of the presentinvention can undergo hydrolysis and taurine release during the lengthof the experiment (24 hours) as well as present activity per se, thusnot being prodrugs but analogs (hybrids).

In order to prove that the reduction in the NO production was not causedby cell death, it was performed a test of cellular viability using thecompounds of the invention when it was, thus, possible prove thevalidity of the previous experiment.

This way, it was performed in vivo tests, described below, and, afterformation of paw's edema, the following compounds were administered:C₁₆H₁₉NO₅S (example 2); C₂₁H₂₁ClN₂O₆S (example 3); C₁₅H₂₃NO₄S(example 1) that demonstrated to present anti inflammatory activity withdosage of 44 mg/kg; 130 mg/Kg and 182 mg/Kg respectively.

The experiments were performed according equimolar experiments formolecular modification products described by BANDARAGE et al. (BANDARAGEet al. “Nitrosothiol esters of diclofenac: Synthesis and pharmacologicalcharacterization as gastrointestinal-sparing prodrugs”, Journal ofMedicinal Chemistry, v. 43, p. 4005-16, 2000); BANOGLU, et al. (BANOGLU,et al. “Amide derivatives of[6-(5-Methil-3-phenylpyrarole-1-yl)-3-(2H)-pyridazinone-2-yl]aceticacids as potential analgesic and anti-inflammatory compounds”, Archivesof the Pharmacy and Pharmaceutical Medicinal Chemistry, v. 337, p. 7-14,2004); RANATUNG, et al. (RANATUNG, et al. “Synthesis andanti-inflammatory activity of series of N-substituted naproxenglycolamides: Nitric oxide-donor naproxen prodrugs”, Bioorganic andMedicinal Chemistry, v. 14, p. 2589-99, 2006); ÖZTÜRK, G. et al.(ÖZTÜRK, G. et al. “New analgesic and antiinflammatory agents4(1H)-pyridinone derivatives”, Europe Journal Medicinal Chemistry, v.37, n. 10 p. 829-34, 2002); LOLLI, et al. (LOLLI, et al. “A new class ofibuprofen derivatives with reduced gastrotoxicity”, Journal of MedicinalChemistry, v. 44, p. 3463-68, 2001). Besides these, a paw's edema testwas performed using taurine as control of its derived compounds, in thedosage of 10 mg/Kg according to HIRATA, T. et al. (HIRATA, T. et al.“Cyclo-oxygenase isozymes in mucosal ulcergenic and functional responsesfollowing barrier disruption in rat stomachs”, British Journal ofPharmacology, v. 122, p. 447-54, 1997).

Experimental Outline

In order to confirm the biological activity of the compounds of thepresent invention, tests were performed according to the pharmacologicalmodel of Wistar rat paw's edema using groups of six animals. It wasverified that, in the reported concentrations, in the presence ofequimolar dosages of the compounds described in the articlesabove-mentioned, such as referral drugs, a reduction of the inflammatoryprocess with the use of the compounds of the invention was observed.

The compounds of the present invention were administered 1 (one) hourprior the inoculation of the irritant agent carragenin in the paws ofthe animals, with the aid of a gavage tube, orally, using water assolvent. The following of the inflammation and anti inflammatoryactivity of the compounds of the invention was performed throughmeasurements of thickness, in millimeters, of the rat's paw.

The control group had the irritant agent carragenin applied to thebottom of their posterior paws and, orally, saline solution. Thetaurine, the ibuprophen, the naproxen and the indometacin wereadministered orally to other groups of animals (positive controls), 60minutes prior to the carragenin (bottom of the paw). Other groups ofanimals had the taurine derived of the present invention (embodimentscorresponding to Examples 1, 2 and 3, respectively—orally) administered60 minutes prior to the carragenin (bottom of the paw).

The posterior paws were measured prior to the treatments and at eachhour, for 6 hours after the carragenin was administered, using anthickness meter, in order to measure their volume (in mm). The resultswere expressed by the difference between the paw's measurement readingsbefore and after the treatments.

As shown by FIGS. 1-4, 6 hours after the compounds of the invention wereadministered; they led to statistically equipotent anti inflammatoryactivity compared to the respective original drugs.

Example 5 Acute Toxicity (Single Dosage) (LD50)

The lethal dosage 50 is differentiated depending on the type of NSAIemployed. For the ibuprophen derived compound (compound 27), the LD₅₀ isof 1,050 mg/Kg; for the naproxen derived compound (compound 63), LD₅₀ isof 1,234 mg/Kg (see MERK INDEX, 2006—14° ed.). Based in these data, theexperiments about the performance of the compounds of the inventionregarding acute toxicity were performed with dosages of 1,000 mg/kg and1,500 mg/kg.

In the experiments of dosage administration of 1,000 mg/kg of each oneof the compounds 27 (synthesis product of taurine with ibuprophen), 63(synthesis product of taurine with naproxen) and 64 (synthesis productof taurine with indometacin) of the invention (corresponding to theembodiments of the examples 1, 2 and 3) were verified that: (i) in thegroup that had compound 27 administered, there was no death in any ofthe tested dosages, presenting values above the ones described foribuprophen, in oral administration toxicity assay (LD₅₀=1,050 mg/Kg);(ii) in the group that had compound 63 administered, in the dosage of1,000 mg/Kg, all animals survived, and in the dosage of 1,500 mg/Kgthere was only 17% of deaths, which is superior to the data found in theliterature for the naproxen (LD₅₀=1,234 mg/Kg); and (iii) in the groupthat had compound 64 administered, in the dosage of 1,000 mg/Kg, noanimal has died and in the dosage of 1,500 mg/Kg, 66% of the populationsurvived to the toxicity assay.

Experimental Outline:

Wistar female rats weighting between 200 and 250 g were used. Thecontrol group had only saline solution administered. To all studiedgroups, dosages of 1,000 and, alternatively, of 1,500 mg/kg wereadministered by gavage feeding.

After fourteen (14) days of administration and observation regarding thetoxicity signs of general kind, effects on motion, behavior, breathing,number of deaths and form of occurrence, the animals that have survivedwere subjected to euthanasia in CO₂ and had their organs such as heart,lungs, kidney, liver and stomach removed and weighted. For the analysisof the results were also considered the body weights.

The difference of the weight of the organs (kidney, heart and liver) ofthe tested animals for the three compounds of the invention is shown inFIGS. 4 to 9, being possible to observe that the results, regardingweight, with the administration of the compounds 28, 64 and 65 of theinvention are substantially close of those obtained with the controlanimals.

Example 6 Gastric Ulcerogenesis

Gastric ulcerogenesis was verified in the same animals of the groupsused for the model of paw's edema.

After 6 hours of the paw's measurement readings, the animals weresubjected to euthanasia in CO₂, and had their stomach removed, cut openin the longitudinal axis and washed with saline solution. In allexperiments, the groups were composed of 6 animals, being kept thedesired therapeutic activity, with absence of gastric lesions, and afterthe LD₅₀ assays, it was concluded that the taurine derived compounds ofthe present invention are safe. It is worth observing, still, that otherorgans, such as lungs and intestine, as well as the macroscopicintegrity of the other organs were kept preserved.

Experimental Outline

Through mucous membrane exposition, it was observed its color andintegrity. In the case of lesions existence, they were counted andmeasured, according to the gastric ulcerogenesis index (G.U.I.) thatfollows numeric criteria for classification of lesions of the gastricmucous membrane: (lesions <1 mm=1; 1.5 to 2.5 mm=2; 2.5 to 3.5 mm=3; 3.5to 4.5 mm=4 and >4.5 mm=5). The obtained results were reported asaverages±E.P.M. The results of the lesion experiment regarding theadministration of the compounds of the present invention (embodimentscorresponding to the Examples 1, 2 and 3) were neither macroscopicallynor microscopically (640×) observed, being reported as lesion index of 0(zero) value. Additionally, with the administration of these compoundsof the invention, it was not observed alterations in the mucousmembrane. FIG. 10 shows this surprising result of no gastric lesion inthe anti inflammatory activity of the compounds of the invention.

All NSAI compounds presented a maximum lesion index, with stipulatedvalue of 5 (five), forming lesions with hemorrhagic spots. It is worthobserving that, for the group of animals of ibuprophen administration,their stomachs presented color alteration of the mucous membrane, asopposed to its correspondent derived compound (compound 27), which didnot present any color alteration in the mucous membrane, keeping itsintegrity.

In all associations, the reduction of the lesion area was accompanied bythe non alteration of the gastric mucous membrane or of hemorrhagicspots.

With no intentions of explaining the reason of the excellent results ofthe molecular modifications in anti inflammatory drugs with theintroduction of transporter as obtained by the compounds of the presentinvention, the advantages presented by these can be attributed,regarding the ulcerogenesis tests, to the differential and perfectedrelease profile or per se activity as shown in FIG. 10.

It is interesting to observe that, in the first hour of the experiment,in the paw's edema test, the anti inflammatory activity of the compoundsof the invention have presented itself as inferior in comparison to theone of the original drugs, but this pattern was totally reversed asshown in FIGS. 1-3. Although the meaning of these results cannot belimited to a theoretical explanation, it can be said that thelatentiation process would explain this behavior of the compounds of thepresent invention, that is, moderate activity in the beginning (afteradministration), with the obtaintion of inferior values of antiinflammatory activity and, in the end, responses similar to therespective original drugs, with the advantage to the drastic reductionof the gastric lesions. However, as seen for aspirin, they could alsopresent activity as structural analogs and including their metabolites.

All of the results were submitted to the variance homogeneity (Levene'stest to certify homogeneity). The results with non-significant p (above0.05) were further submitted to Analysis of Variance (ANOVA), followedby the multiple comparisons test (post hoc analysis) as theNewman-Keuls' test; and it was only considered the values of p when theywere equal or inferior to 0.05.

All of the publications and patent applications mentioned in thedescription are indicatives of the level of those specialists in thetechnique to which the invention relates to. All the publications andpatent applications are incorporated herein by references to the sameextent as if each individual publication or each patent application werespecifically and individually indicated to be incorporated by reference.

Even though the precedent invention has been described in some detailsby means of illustration and examples for clarity and understandingpurposes, it will be obvious that certain changes and modifications canbe performed within the scope of the claims that accompanies thisdescription.

1-16. (canceled)
 17. A process for preparing a taurine derivativecompound, comprising reacting taurine with a non-steroidal antiinflammatory (NSAI) compound in the presence of a catalyst in an organicmedia, wherein the taurine derivative compound is a compound of Formula(I)

and its salts, solvates, hydrates, enantiomers, diasteroisomers andpolymorphs: in which R is selected from the group consisting of:2-[2-(2,6-dichlorophenylamino)phenyl]acetic acid,2-[(2,6-dichloro-3-methylphenyl)amino]benzoic acid,2-{[3-(trifluoromethyl)phenyl]amino}nicotinic acid,2-[(2,3-dimethylphenyl)amino]benzoic acid,[2-(2,4-dichlorophenoxy)phenyl]acetic acid,2-[(3-chloro-2-methylphenyl)amino]benzoic acid,2-[(1,2-diphenyl-hydrazine) carbonyl]hexanoic acid,4-[(4-butyl-3,5-dioxo-1,2-diphenylpyrazolidin-4-yl)methoxy]-4-oxobutanoicacid, (1,3,4-triphenyl-1H-pyrazol-5-yl)acetic acid,[3-(4-chlorophenyl)-1-phenyl-1H-pyrazol-4-yl]acetic acid,[(1-benzyl-1H-indazole-3-yl)oxy]acetic acid,[4-(4-chlorophenyl)-2-phenyl-1,3-thiazol-5-yl]acetic acid,[2-(4-chlorophenyl)-1,3-thyazol-4-yl]acetic acid,3-(4,5-diphenyl-1,3-oxazol-2-yl)propanoic acid,[1-(4-chlorophenyl)-2,5-dimethyl-1H-pyrol-3-yl]acetic acid,2-amino-6-benzyl-4,5,6,7-tetrahydrothyen[2,3-c]pyridine-3-carboxylicacid, 2-(2-hydroxybenzoylic)acid, [2-(aminocarbonyl)phenoxy]acetic acid,2,5-dihydroxybenzoic acid, 2-(acetyloxy)benzoic acid,2-(sulphooxy)benzoic acid, 2-[(2-hydroxybenzoyl)oxy]benzoic acid,2-[(2-phenylethyl)amino]benzoic acid,5-[(2-phenyl-4,5-dihydro-3H-benzo[e]-1H-indole-2-(2-hydroxybenzoicacid), 2′,4′-difluoro-4-hydroxy-1,1′-diphenyl-3-carboxilic acid,2-(4-isobutylphenyl) butanoic acid, 2-(4-isobutylphenyl) propanoic acid,2-[4-(thyen-2-yl-carbonyl)phenyl]propanoic acid, 2-(3-phenoxyphenyl)propanoic acid, chloro(3-chloro-4-cyclo-hexylphenyl)acetic acid,4-(3-chloro-4-cyclo-hexyl phenyl)-4-oxobutanoic acid,6-chloro-5-cyclo-hexylindan-1-carboxilic acid,2-{4-[(2-methylprop-2-enyl)amino]phenyl}propanoic acid,2-(5-benzoylthyen-2-yl) propanoic acid,5-benzoyl-2,3-dihydro-1H-pyrolizine-1-carboxilic acid,2-[2-(4-fluorophenyl)-1,3-benzoxazol-5-yl]propanoic acid,2-[2-(4-chlorophenyl)-1,3-benzoxazol-5-yl]propanoic acid,2-(3-benzoylphenyl) propanoic acid, 2-(4-imidazo[1,2-a]pyridin-2-ylphenyl) propanoic acid,[1-methyl-5-(4-methylbenzoyl)-1H-pyrol-2-yl]acetic acid,[5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrol-2-yl]acetic acid,2-[3-chloro-4-(2,5-dihydro-1H-pyrol-1-yl)phenyl]propanoic acid,(11-oxo-6,11-dihydroxibenzo[b,e]oxepin-2-yl)acetic acid,2-(2-fluoro-1,1′-diphenyl-4-yl) propanoic acid,[4-(allyoxy)-3-chlorophenyl]acetic acid,2-[4-(1-oxo-1,3-dihydro-2H-isoindoie-2-yl)phenyl]propanoic acid,2-[4-(2,5-dihydrothyen-2-yl carbonyl)phenyl]propanoic acid,2-(5H-chromeno[2,3-b]pyridin-7-yl) propanoic acid,4-(1,1′-diphenyl-4-yl)-4-oxobutanoic acid, 1,1′-diphenyl-4-yl aceticacid, 2-(6-methoxy-2-naphtyl) propanoic acid,[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-yl]acetic acid,{5-methoxy-2-methyl-1-[(2E)-3-phenylprop-2-enoy]-1H-indole-3-yl}aceticacid,({[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-yl]acetyl}oxy)aceticacid, (1,8-diethyl-1,3,4,9-tetrahydrofurane[3,4-b]indole-1-yl)aceticacid,{(1E)-5-fluoro-2-methyl-1-[4-(methylsulphinyl)benzylidene]-1H-inden-3-yl}aceticacid, and 2-(6-chloro-9H-carbazol-2-yl) propanoic acid.
 18. The processaccording to claim 17, wherein the process is a process of latentiation.19. The process according to claim 17, wherein the NSAI compound isselected from the group consisting of: salycilates, pyrazolons and itsanalogs, derived indoleacetics, derived arilacetics, derivedarylpropionics, oxycams, and phenamates.
 20. The process according toclaim 19, wherein the NSAI compound is selected from the groupconsisting of: 2-[2-(2,6-dichlorophenylamino)phenyl]acetic acid,2-[(2,6-dichloro-3-methylphenyl)amino]benzoic acid,2-{[3-(trifluoromethyl)phenyl]amino}nicotinic acid,2-[(2,3-dimethylphenyl)amino]benzoic acid,[2-(2,4-dichlorophenoxy)phenyl]acetic acid,2-[(3-chloro-2-methylphenyl)amino]benzoic acid,2-[(1,2-diphenyl-hydrazine) carbonyl]hexanoic acid,4-[(4-butyl-3,5-dioxo-1,2-diphenylpyrazolidin-4-yl)methoxy]-4-oxobutanoicacid, (1,3,4-triphenyl-1H-pyrazol-5-yl)acetic acid,[3-(4-chlorophenyl)-1-phenyl-1H-pyrazol-4-yl]acetic acid,[(1-benzyl-1H-indazole-3-yl)oxy]acetic acid,[4-(4-chlorophenyl)-2-phenyl-1,3-thiazol-5-yl]acetic acid,[2-(4-chlorophenyl)-1,3-thyazol-4-yl]acetic acid,3-(4,5-diphenyl-1,3-oxazol-2-yl)propanoic acid,[1-(4-chlorophenyl)-2,5-dimethyl-1H-pyrol-3-yl]acetic acid,2-amino-6-benzyl-4,5,6,7-tetrahydrothyen[2,3-c]pyridine-3-carboxylicacid, 2-(2-hydroxybenzoic)acid, [2-(aminocarbonyl)phenoxy]acetic acid,2,5-dihydroxybenzoic acid, 2-(acetyloxy)benzoic acid,2-(sulphooxy)benzoic acid, 2-[(2-hydroxybenzoyl)oxy]benzoic acid,2-[(2-phenylethyl)amino]benzoic acid,5-[(2-phenyl-4,5-dihydro-3H-benzo[e]-1H-indole-2-(2-hydroxybenzoicacid), 2′,4′-difluoro-4-hydroxy-1,1′-diphenyl-3-carboxilic acid,2-(4-isobutylphenyl) butanoic acid, 2-(4-isobutylphenyl) propanoic acid,2-[4-(thyen-2-yl-carbonyl)phenyl]propanoic acid, 2-(3-phenoxyphenyl)propanoic acid, chloro(3-chloro-4-cyclo-hexylphenyl)acetic acid,4-(3-chloro-4-cyclo-hexyl phenyl)-4-oxobutanoic acid,6-chloro-5-cyclo-hexylindan-1-carboxilic acid,2-{4-[(2-methylprop-2-enyl)amino]phenyl}propanoic acid,2-(5-benzoylthyen-2-yl) propanoic acid,5-benzoyl-2,3-dihydro-1H-pyrolizine-1-carboxilic acid,2-[2-(4-fluorophenyl)-1,3-benzoxazol-5-yl]propanoic acid,2-[2-(4-chlorophenyl)-1,3-benzoxazol-5-yl]propanoic acid,2-(3-benzoylphenyl) propanoic acid, 2-(4-imidazo[1,2-a]pyridin-2-ylphenyl) propanoic acid,[1-methyl-5-(4-methylbenzoyl)-1H-pyrol-2-yl]acetic acid,[5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrol-2-yl]acetic acid,2-[3-chloro-4-(2,5-dihydro-1H-pyrol-1-yl)phenyl]propanoic acid,(11-oxo-6,11-dihydroxibenzo[b,e]oxepin-2-yl)acetic acid,2-(2-fluoro-1,1′-diphenyl-4-yl) propanoic acid,[4-(allyloxy)-3-chlorophenyl]acetic acid,2-[4-(1-oxo-1,3-dihydro-2H-isoindole-2-yl)phenyl]propanoic acid,2-[4-(2,5-dihydrothyen-2-yl carbonyl)phenyl]propanoic acid,2-(5H-chromeno[2,3-b]pyridin-7-yl) propanoic acid,4-(1,1′-diphenyl-4-yl)-4-oxobutanoic acid, 1,1′-diphenyl-4-yl aceticacid, 2-(6-methoxy-2-naphtyl) propanoic acid,[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-yl]acetic acid,{5-methoxy-2-methyl-1-[(2E)-3-phenylprop-2-enoyl]-1H-indole-3-yl}aceticacid,({[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-yl]acetyl}oxy)aceticacid, (1,8-diethyl-1,3,4,9-tetrahydrofurane[3,4-b]indole-1-yl)aceticacid,{(1E)-5-fluoro-2-methyl-1-[4-(methylsulphinyl)benzylidene]-1H-inden-3-yl}aceticacid, and 2-(6-chloro-9H-carbazol-2-yl) propanoic acid.
 21. The processaccording to claim 17, wherein the NSAI compound is selected from thegroup consisting of: 2-(4-isobutylphenyl) butanoic acid,2-(6-methoxy-2-naphtyl) propanoic acid and[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-yl]acetic acid. 22.The process according to claim 17, wherein the catalyst is selected fromgroup consisting of: diethylcyanophosphonate, 1-hydroxybenzotriazole,carbodiimides, triethyamine, imidazole, pyrazole, 1,2,4-triazole,4-dimethyl aminopyridine, and pyridine.
 23. The process according toclaim 17, wherein the catalyst is diethylcyanophosphonate.
 24. Theprocess according to claim 17, wherein the organic media is an organicsolvent selected from the group consisting of acetone, tetrahydrofuranand dimethylformamide.
 25. The process according to claim 17, whereinthe process is performed at room temperature and pH is highly alkaline.26. A pharmaceutical composition comprising: (a) apharmacologically-effective quantity of at least one taurine derivativecompound; (b) optionally a pharmacologically-effective quantity of atleast one active principle for the treatment of a medical conditioninvolving an inflammatory disturbance; and (c) a pharmaceuticallyacceptable vehicle, wherein the taurine derivative compound is acompound of Formula (I)

and its salts, solvates, hydrates, enantiomers, diasteroisomers andpolymorphs: in which R is selected from the group consisting of:2-[2-(2,6-dichlorophenylamino)phenyl]acetic acid,2-[(2,6-dichloro-3-methylphenyl)amino]benzoic acid,2-{[3-(trifluoromethyl)phenyl]amino}nicotinic acid,2-[(2,3-dimethylphenyl)amino]benzoic acid,[2-(2,4-dichlorophenoxy)phenyl]acetic acid,2-[(3-chloro-2-methylphenyl)amino]benzoic acid,2-[(1,2-diphenyl-hydrazine) carbonyl]hexanoic acid,4-[(4-butyl-3,5-dioxo-1,2-diphenylpyrazolidin-4-yl)methoxy]-4-oxobutanoicacid, (1,3,4-triphenyl-1H-pyrazol-5-yl)acetic acid,[3-(4-chlorophenyl)-1-phenyl-1H-pyrazol-4-yl]acetic acid,[(1-benzyl-1H-indazole-3-yl)oxy]acetic acid,[4-(4-chlorophenyl)-2-phenyl-1,3-thiazol-5-yl]acetic acid,[2-(4-chlorophenyl)-1,3-thyazol-4-yl]acetic acid,3-(4,5-diphenyl-1,3-oxazol-2-yl)propanoic acid,[1-(4-chlorophenyl)-2,5-dimethyl-1H-pyrol-3-yl]acetic acid,2-amino-6-benzyl-4,5,6,7-tetrahydrothyen[2,3-c]pyridine-3-carboxylicacid, 2-(2-hydroxybenzoylic)acid, [2-(aminocarbonyl)phenoxy]acetic acid,2,5-dihydroxybenzoic acid, 2-(acetyloxy)benzoic acid,2-(sulphooxy)benzoic acid, 2-[(2-hydroxybenzoyl)oxy]benzoic acid,2-[(2-phenylethyl)amino]benzoic acid,5-[(2-phenyl-4,5-dihydro-3H-benzo[e]-1H-indole-2-(2-hydroxybenzoicacid), 2′,4′-difluoro-4-hydroxy-1,1′-diphenyl-3-carboxilic acid,2-(4-isobutylphenyl) butanoic acid, 2-(4-isobutylphenyl) propanoic acid,2-[4-(thyen-2-yl-carbonyl)phenyl]propanoic acid, 2-(3-phenoxyphenyl)propanoic acid, chloro(3-chloro-4-cyclo-hexylphenyl)acetic acid,4-(3-chloro-4-cyclo-hexyl phenyl)-4-oxobutanoic acid,6-chloro-5-cyclo-hexylindan-1-carboxilic acid,2-{4-[(2-methylprop-2-enyl)amino]phenyl}propanoic acid,2-(5-benzoylthyen-2-yl) propanoic acid,5-benzoyl-2,3-dihydro-1H-pyrolizine-1-carboxilic acid,2-[2-(4-fluorophenyl)-1,3-benzoxazol-5-yl]propanoic acid,2-[2-(4-chlorophenyl)-1,3-benzoxazol-5-yl]propanoic acid,2-(3-benzoylphenyl) propanoic acid, 2-(4-imidazo[1,2-a]pyridin-2-ylphenyl) propanoic acid,[1-methyl-5-(4-methylbenzoyl)-1H-pyrol-2-yl]acetic acid,[5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrol-2-yl]acetic acid,2-[3-chloro-4-(2,5-dihydro-1H-pyrol-1-yl)phenyl]propanoic acid,(11-oxo-6,11-dihydroxibenzo[b,e]oxepin-2-yl)acetic acid,2-(2-fluoro-1,1′-diphenyl-4-yl) propanoic acid,[4-(allyloxy)-3-chlorophenyl]acetic acid,2-[4-(1-oxo-1,3-dihydro-2H-isoindole-2-yl)phenyl]propanoic acid,2-[4-(2,5-dihydrothyen-2-yl carbonyl)phenyl]propanoic acid,2-(5H-chromeno[2,3-b]pyridin-7-yl) propanoic acid,4-(1,1′-diphenyl-4-yl)-4-oxobutanoic acid, 1,1′-diphenyl-4-yl aceticacid, 2-(6-methoxy-2-naphtyl) propanoic acid,[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-yl]acetic acid,{5-methoxy-2-methyl-1-[(2E)-3-phenylprop-2-enoyl]-1H-indole-3-yl}aceticacid,({[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-yl]acetyl}oxy)aceticacid, (1,8-diethyl-1,3,4,9-tetrahydrofurane[3,4-b]indole-1-yl)aceticacid,{(1E)-5-fluoro-2-methyl-1-[4-(methylsulphinyl)benzylidene]-1H-inden-3-yl}aceticacid, and 2-(6-chloro-9H-carbazol-2-yl) propanoic acid.
 27. Thepharmaceutical composition according to claim 26, wherein the at leastone taurine derivative compound is selected from the group consistingof: 2-{2-[2-(2,6-dichlorophenylamino) phenyl]acetamide}ethanesulfonicacid, 2-{[(2,6-dichloro-3-methylphenyl)aminobenzoil]amide}ethanesulfonicacid,2-{[3-(trifluoromethyl)phenyl]amino}nicotinoyl]amide}ethanesulfonicacid, 2-{[(2,3-dimethylphenyl)amino]benzoyl]amide}ethanesulfonic acid,2-{[(2,4-dichlorophenoxy)phenyl]acetyl]amide}ethanesulfonic acid,2-{[(3-chloro-2-methylphenyl)amino]benzoyl]amide}ethanesulfonic acid,2-{[(1,2-diphenyl-hydrazino) carbonyl]hexanoyl]amide}ethanesulfonicacid, 4-{[(4-butyl-3,5-dioxo-1,2-diphenylpirazolidin-4-yl)methoxy]-4-oxobutanoyl]amide}ethanesulfonic acid,{[(1,3,4-triphenyl-1H-pirazol-5-yl)acetyl]amide}ethanesulfonic acid,{[[3-(4-chlorophenyl)-1-phenyl-1H-pirazol-4-yl]acetyl]amide}ethanesulfonicacid, {[(1-benzyl-1H-indazol-3-yl)oxy]acetyl]amide}ethanesulfonic acid,{[[4-(4-chlorophenyl)-2-phenyl-1,3-thiazol-5-yl]acetyl]amide}ethanesulfonicacid, {[[2-(4-chlorophenyl)-1,3-thiazol-4-yl]acetyl]amide}ethanesulfonicacid, 3-{[(4,5-diphenyl-1,3-oxazol-2-yl)propanoyl]amide}ethanesulfonicacid,{[[1-(4-chlorophenyl)-2,5-dimethyl-1H-pyrol-3-yl]acetyl]amide}ethanesulfonicacid,2-{[amino-6-benzyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylyl]amide}ethanesulfonicacid, [2-(2-hydroxybenzoyl)amide]ethanesulfonic acid,{[[2-(aminocarbonyl)phenoxy]acetyl]amide}ethanesulfonic acid,[(2,5-dihydroxybenzoyl)amide]ethanesulfonic acid,{[2-(acetyloxy)benzoyl]amide}ethanesulfonic acid,{[2-(sulphooxy)benzoyl]amide}ethanesulfonic acid,2-{[(2-hydroxybenzoyl)oxy]benzoyl]amide}ethanesulfonic acid,2-{[(2-phenylethyl)amino]benzoyl]amide}ethanesulfonic acid,5-{[(2-phenyl-4,5-dihydro-3H-benzo[e]-1H-indole-2-(2-hydroxybenzoyl)amide]}ethanesulfonicacid,[(2′,4′-difluoro-4-hydroxy-1,1′-diphenyl-3-carboxylyl)amide]ethanesulfonicacid, 2-{[2-(4-isobuthylphenyl) butanoyl]amide}ethanesulfonic acid,[2-(4-isobuthylphenyl) propanoyl]amide ethanesulfonic acid,{2-[4-(thien-2-yl-carbonyl)phenyl]propanoyl}amide ethanesulfonic acid,{2-(3-phenoxyphenyl) propanoyl}amide ethanesulfonic acid,[chloro(3-chloro-4-cyclo-hexylphenyl)acetyl]amide ethanesulfonic acid,[4-(3-chloro-4-cyclo-hexyl phenyl)-4-oxobutanoyl]amide ethanesulfonicacid, (6-chloro-5-cyclo-hexylindane-1-carboxyl) amide ethanesulfonicacid, 2-{4-[(2-methylprop-2-enil)amino]phenyl-propanoyl}amideethanesulfonic acid, [2-(5-benzoylthien-2-yl) propanoyl]amideethanesulfonic acid, (5-benzoyl-2,3-dihydro-1H-pyrolizine-1-carboxyl)amide ethanesulfonic acid,{2-[2-(4-fluorophenyl)-1,3-benzoxazol-5-yl]propanoyl}amideethanesulfonic acid,{2-[2-(4-chlorophenyl)-1,3-benzoxazol-5-yl]propanoyl}amideethanesulfonic acid, [2-(3-benzoylphenyl) propanoyl]amide ethanesulfonicacid, [2-(4-imidazo[1,2-a]pyridin-2-yl phenyl) propanoyl]amideethanesulfonic acid,{[1-methyl-5-(4-methylbenzoyl)-1H-pyrol-2-yl]acetyl}amide ethanesulfonicacid, {[5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrol-2-yl]acetyl}amideethanesulfonic acid,{2-[3-chloro-4-(2,5-dihydro-1H-pyrol-1-yl)phenyl]propanoyl}amideethanesulfonic acid,[(11-oxo-6,11-dihydroxibenzo[b,e]oxepin-2-yl)acetyl]amide ethanesulfonicacid, [2-(2-fluoro-1,1′-diphenyl-4-yl) propanoyl]amide ethanesulfonicacid, {[4-(allyloxy)-3-chlorophenyl]acetyl}amide ethanesulfonic acid,{2-[4-(1-oxo-1,3-dihydro-2H-isoindole-2-yl)phenyl]propanoyl}amideethanesulfonic acid, {2-[4-(2,5-dihydrothien-2-ylcarbonyl)phenyl]propanoyl}amide ethanesulfonic acid,2-{[(5H-chromeno[2,3-b]pyridin-7-yl) propanoyl]amide}ethanesulfonicacid, 4-{[(1,1′-biphenyl-4-yl)-4-oxobutanoyl]amide}ethanesulfonic acid,[(1,1′-biphenyl-4-yl acetyl)amide]ethanesulfonic acid,2-{[2-(6-methoxy-2-naphthyl) propanoyl]amide}ethanesulfonic acid,[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-yl]acetyl]amide}ethanesulfonicacid,{[(5-methoxy-2-methyl-1-[(2E)-3-phenylprop-2-enoyl]-1H-indole-3-yl)acetyl]amide}ethanesulfonicacid,[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-yl]acetyl}oxy)acetyl]amide}ethanesulfonicacid,{[(1,8-diethyl-1,3,4,9-tetrahydrofuran[3,4-b]indole-1-yl)acetyl]amide}ethanesulfonicacid,{[((1E)-5-fluoro-2-methyl-1-[4-(methylsulphonyl)benzylidene]-1H-inden-3-yl)acetyl]amide}ethanesulfonicacid, and 2-{[(6-chloro-9H-carbazol-2-yl) propanoyl]amide}ethanesulfonicacid.
 28. The pharmaceutical composition according to claim 26, whereinthe at least one taurine derivative compound is selected from the groupconsisting of: 2-{2-[2-(2,6-dichlorophenylamino)phenyl]acetamide}ethanesulfonic acid; [2-(4-isobuthylphenyl)propanoyl]amide ethanesulfonic acid; 2-{[2-(6-methoxy-2-naphthyl)propanoyl]amide}ethanesulfonic acid;(5-benzoyl-2,3-dihydro-1H-pyrolizine-1-carboxyl) amide ethanesulfonicacid; 2-{[2-(4-isobutylphenyl) butanoyl]amino}ethanesulfonic acid; and[1-(4-chlorobenzoyl)-5-metoxy-2-methyl-1H-indole-3-yl]acetyl]amino}ethanesulfonicacid.